Cystic fibrosis is the most common lethal, inherited disease of Caucasian people with an incidence of 1 in 2,000 live births. The basic underlying abnormality in CF has not yet been determined. Our recent studies have demonstrated an abnormal fucose metabolism in skin fibroblasts and serum of patients with CF when compared to age, sex and race matched controls. The abnormal fucose metabolism is manifest by 1) altered carbohydrate composition of surface membrane components in CF skin fibroblasts 2) increased activity of alpha-L-fucosidase in CF skin fibroblasts 3) decreased activity of alpha-L-fucosidase in CF serum. In addition, gel electrophoresis of isolated fibroblast surface membranes reveals a protein band of 145,000 daltons which is unique to the CF membranes. The primary objective of the proposed research is to define the relationship of these abnormalities of fucose metabolism to the pathogenesis of CF. The observations will be extended to other cell types and to additional CF patients, heterozygotes and controls. The altered carbohydrate composition will be precisely defined by enzymatic sequencing of membrane glycopeptides from skin fibroblasts. Isoelectric focusing will be used to determine the isozymes of alpha-L-fucosidase which are prevalent in CF. The uptake and secretion of alpha-L-fucosidase in cultured fibroblasts will be examined for an abnormality in a specific membrane receptor. The 145,000 dalton CF membrane protein will be further characterized. It is anticipated that the ultimate recognition of the biochemical lesion in CF would lead to a more rational therapy and provide an accurate method for heterozygote detection.